tbuckley/cabot-search huggingface dataset:
BIOM-33. TEMPORAL HETEROGENEITY OF DNA METHYLATION SUBCLASSES BETWEEN MATCHED NEWLY DIAGNOSED AND RECURRENT IDH-WILDTYPE GLIOBLASTOMA
Authors: Richard Drexler, Ulrich Schüller, Alicia Eckhardt, Thomas Sauvigny, Tammo Ricklefs, Helena Bode, Robin Khatri, Fabian Hausmann, Sonja Hänzelmann, Tobias Huber, Stefan Bonn, Katrin Lamszus, Manfred Westphal, Lasse Dührsen, Franz Ricklefs
Journal: Neuro-Oncology (2022)

Abstract Spatiotemporal heterogeneity is a major factor contributing to the devastating prognosis of isocitrate-dehydrogenase (IDH)-wildtype glioblastoma. Genome-wide DNA methylation profiling allows the stratification into several DNA methylation subgroups of IDH-wildtype glioblastoma, which were shown to have a spatial heterogeneity in newly diagnosed tumors. However, the temporal heterogeneity and its clinical relevance of DNA methylation subgroups remains inconclusive. Tumor tissue obtained from first and recurrence surgery of 31 patients diagnosed with IDH-wildtype glioblastoma was subjected to DNA methylation profiling. DNA methylation profiles were analyzed for temporal heterogeneity and correlated with clinical data, survival outcome and copy number variations. In addition, deconvolution of immune cells and unsupervised hierarchical clustering using pairwise Pearson correlation coefficients of the 10.000 most variable CpG features was performed. Of all patients with matched tumor tissue, 4 (12.9%) patients had a non-matching brain tumor classifier output at recurrence. Within the remaining 27 patients, a transition of the dominant DNA methylation subclass was observed in 8 (29.6%) glioblastomas with a most frequent transition to the mesenchymal subclass (62.5%). A subclass transition was more likely after incomplete removal of contrast-enhanced tumor parts at first surgery (p = 0.04). Tumor location, adjuvant treatment, and time between primary and recurrence surgery did not influence the transition. Immune cell proportions from deconvolution data, tumor purity or specific CpG sites were not correlated with a subclass transition. Survival analyses revealed a comparable outcome for patients with or without subclass transition. Our findings demonstrate the temporal heterogeneity of DNA methylation subclasses in 29.6% of IDH-wildtype glioblastoma. We identified clinical factors and showed that a subclass transition did not impact the survival outcome. However, a possible DNA methylation subclass transition must be taken into consideration for future targeted therapies at recurrence.
SURG-02. INTRAOPERATIVE RADIOTHERAPY FOR BRAIN METASTASES: EVALUATION OF ELECTROCORTICOGRAPHY AND PERI-OPERATIVE SEIZURE RISK
Authors: Christopher Cifarelli
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Intraoperative radiotherapy (IORT) has emerged as a viable tool for consolidation of surgery and radiation for brain metastases into a single episode of care, but its relative novelty compared to SRS or fractionated radiotherapy warrants evaluation of its safety. While post-operative seizure risk is typically minimal with the use of anti-epileptic drugs during the peri-operative phase, the risk of intra-operative epileptiform discharge remains unknown. METHODS Five consecutive cases of surgically resected brain metastases treated with IORT underwent electrocorticography via direct cortical electrode recordings adjacent to the resection cavity with paddle electrodes used for mapping of phase reversal. Continuous recordings were made before, during, and after radiation delivery and analyzed for evidence of radiation-associated changes. RESULTS No evidence of significant electrophysiological change was noted in any of the cases, nor was there any clinical evidence of seizure in the immediate peri-operative period. These data represent the first direct cortical recordings in human subjects during the delivery of radiation. CONCLUSIONS In this small cohort of IORT treated resected brain metastases, the delivery of intra-operative radiation does not appear to impact cortical activity or precipitate post-operative seizures. Further studies are needed to determine the long-term incidence of treatment associated changes if they exist.
IMMU-05. THE INFLUENCE OF THE KETOGENIC DIET ON THE IMMUNE TOLERANT MICROENVIRONMENT IN GLIOBLASTOMA
Authors: Pravin Kesarwani, Yi Zhao, Shiva Kant, C Ryan Miller, Prakash Chinnaiyan
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) represents a particularly aggressive and immune-resistant cancer. Preclinical investigations have identified the anti-tumor activity of a ketogenic diet (KD) in GBM, potentially being used as a tool to target its glycolytic phenotype. Since immune cells in the tumor have a similar reliance upon nutrients to perform their individual functions, we sought to determine if the KD influenced the immune landscape of GBM. Utilizing genetically-engineered murine GBM tumor cells orthotopically implanted in immune-competent mice, we demonstrate that KD improved survival in GBM. Immunophenotyping of tumors identified a novel role KD plays in macrophage polarization, with a paradoxical 50% increase in immune-suppressive M2-macrophages and a decrease in pro-inflammatory M1-macrophages. We recapitulated KD in vitro using a modified cell culture based on comprehensive metabolomic profiling of serum in KD-fed mice. Consistent with in vivo studies, murine macrophages cultured in these conditions skewed polarization towards the M2-phenotype with immune-suppressive properties. We went on to mechanistically link these findings to the activation of transcription factor PPARg. Although anti-tumor activity was observed in mice fed a KD, we hypothesized this parallel increase in M2 macrophage polarization tempered its potential therapeutic benefit. Colony-stimulating factor 1 (CSF-1) plays a central role in macrophage differentiation, and CSF-1R inhibition is actively being investigated as a strategy to skew their polarization towards an M1-phenotype. Therefore, we tested a combination of KD with the brain-penetrant CSF-1R inhibitor BLZ945. Consistent with our hypothesis, this combination demonstrated a striking improvement in survival (p = 0.0004), with 50% of mice achieving long-term survival ( &amp;gt; 50 days). Correlative studies confirmed the capacity of BLZ945 to normalize KD-induced increases in M2s, and the combination induced an increase of anti-tumor iNOS+M1s. Combinatorial strategies using agents designed to modulate macrophage polarization represent a rational approach to improve the anti-tumor activity of KD in GBM.
QLTI-25. CREATING A CHEMOTHERAPY COMPETENCY METRIC FOR NEURO-ONCOLOGY FELLOWSHIP TRAINEES
Authors: Katherine B Peters, Mallika Patel, Maciej Mrugala
Journal: Neuro-Oncology (2022)

Abstract Neuro-oncology fellowship trainees have varied academic backgrounds before subspecialty certification with most completing neurology residency ( &amp;gt; 90%) and a minority coming from medical oncology and neurosurgery programs. Given the variability in background and training of fellows, concerns about competency, particularly in prescribing chemotherapy and understanding associated toxicities, need to be addressed. Providing a metric to track and assess competency can enhance trainees’ skills and bolster confidence during a neuro-oncology fellowship. In an IRB-exempt quality improvement project, we developed a competency test that was primarily case-based and guided knowledge of treatment indications, dosing, and management of associated toxicities. All questions were created based on NCCN guidelines and linked to a quality metric from ASCO-QOPI. Question content included 1. Prescribing, 2. Prescription review 3. Planning management, 4. Communicating information, 5. Drug dose calculation skills, 6. Adverse drug reactions, 7. Drug monitoring, and 8. Data interpretation. At the start of the fellowship, trainees took a pre-assessment test with a validated Likert scale for self-efficacy/confidence. These tests were scored, and directed elements were delivered via didactics to fellows by practicing neuro-oncologist and clinical pharmacist. The same assessments were performed at 6 and 12 months. All tests were scored and compared to the level of self-efficacy/confidence. Four fellows were included in this project across two institutions. Higher level of proficiency correlated with a higher level of self-reported confidence at the pre-assessment time point. Assessment at six months revealed an improvement in test scores and associated confidence and this trend continued at fellowship completion. This metric is the first known tool to evaluate chemotherapy competency and confidence in neuro-oncology fellows. Performance and self-efficacy/confidence are positively linked. This chemotherapy competency metric can be introduced to all neuro-oncology fellowship programs and used for national certification.
RADT-11. CLINICAL OUTCOMES IN THE MANAGEMENT OF MELANOMA BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY AND ANTI-PD-1+CTLA-4
Authors: Joseph Tang, Ammoren Dohm, Hruday Kalagotla, Menal Bhandari, Youngchul Kim, Jasmine Graham, Nikhil Khushalani, Peter Forsyth, Arnold Etame, James Liu, Nam Tran, Michael Vogelbaum, Michael Yu, Kamran Ahmed, Daniel Oliver
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Anti-PD-1+CTLA-4 therapy has revolutionized melanoma brain metastases (MBM) treatment. Prospective trials show higher response in asymptomatic versus symptomatic patients. We evaluated clinical outcomes in MBM treated with stereotactic radiosurgery (SRS) and anti-PD-1+CTLA-4. METHODS Patients were included if MBM were diagnosed and treated with SRS within 3 months of anti-PD-1+CTLA-4, and this was their last course of systemic treatment. Endpoints of this study were distant MBM control, MBM local control (LC) defined as less than 20% volume increase on follow-up MRI, and overall survival (OS) from SRS. Adverse advents were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS 29 patients with 122 MBM treated over 40 SRS sessions between 2015-2020 were identified. Median SRS dose: 24 Gy (range: 15-24). Median MBM diameter: 0.6 cm (range: 0.3-2.9). Median follow-up using reverse Kaplan-Meier (KM) method: 19.3 months (interquartile range: 14.6-38.4).Six-, twelve-, and eighteen-month KM distant MBM control rates were 51%, 42%, 42%, respectively. LC rates: 90%, 86%, 85%. OS rates: 76%, 68%, 56%. 17 patients (59%) were asymptomatic and 12 (41%) symptomatic. KM distant MBM control and OS for asymptomatic and symptomatic patients were not significant; p=0.61 and p=0.67, respectively.On univariate analysis (UVA), Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) 0-1 was associated with increased risk of distant MBM failure versus DS-GPA 3.5-4 (hazard ratio (HR): 9.8, 95% confidence interval (CI) 1.9-51.5, p=0.007). UVA showed decreased OS with increased number of organs with metastases at diagnosis (HR:12, 95% CI 2.0-83.1, p=0.0075).2 lesions (1.6%) developed symptomatic radiation necrosis requiring steroids; 10 lesions developed grade 3 edema (8%); 13 patients experienced grade 1-2 fatigue and/or headache (45%); no patients experienced grade &amp;gt;3 events. CONCLUSION Combination SRS and anti-PD-1+CTLA-4 in MBM shows durable intracranial control with similar outcomes between asymptomatic and symptomatic patients with acceptable toxicity. Further study is warranted.
CTNI-66. THE PREOPERATIVE BRAIN IRRADIATION IN GLIOBLASTOMA (POBIG) STUDY: A NOVEL TREATMENT PARADIGM TO IMPROVE OUTCOMES?
Authors: Gerben Borst, Mueez Waqar, Catherine McBain, William Beasley, Christopher Golby, Petra Hamerlik, Tina Karabatsou, Matthew Bailey, Pietro D’Urso, Ibrahim Djoukhadar, Leila Akkari, Jenny Richardson, Lauren Hewitt, Daniel DuPlessis, Claire O’Leary, Richard Jackson, David Coope, Federico Roncaroli
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE The Preoperative Brain Irradiation in Glioblastoma (POBIG) study evaluates for the first time the safety, feasibility, and impact of single fraction preoperative radiotherapy in newly diagnosed glioblastoma patients. METHODS Operable patients with a radiological diagnosis of glioblastoma, by consensus of a multidisciplinary tumor board including two dedicated neuro-radiologists, are screened for the study. Anatomical and functional MRI sequences are acquired for further tumor characterization and preoperative radiotherapy planning. Radiotherapy is delivered approximately two weeks after the initial screening. Radiation targets the macroscopic and microscopic tumor region at risk of being left behind during surgery and spares at least 2cc tumor volume being debulked to safeguard unperturbed and clinically relevant tissue examination and molecular profiling. The study dose-escalates (from 8Gy to 14Gy) based on the time-to-event Continual Reassessment Methodology. Subsequently, patients undergo surgical debulking followed by postoperative fractionated radiotherapy 60Gy/30fr with concurrent temozolomide. RESULTS The first POBIG study patient underwent preoperative radiotherapy followed by a subtotal resection of a left posterior fronto-opercular tumor and completed the postoperative chemoradiotherapy. Screening, study consent, MRI imaging and analysis, radiotherapy planning and delivery until surgery can be achieved within three weeks from screening while maintaining adequate and personalized patient communication. There were no surgical or radiotherapy delays or complications. During surgery, we successfully sampled unirradiated and irradiated tumor regions. The radiotherapy field covered the whole remnant tumor, and image-guided obtained tumor samples and imaging analysis showed clear evidence of differential radiation-induced changes. CONCLUSION We successfully initiated a new treatment strategy of preoperative radiotherapy for glioblastoma patients. The first patient completed the treatment, and the study is now open for further recruitment. Paired tumor sampling and advanced imaging analysis showed promising results. The POBIG study offers a unique opportunity for a paradigm shift towards personalized treatment regimens, hopefully leading to better outcomes.
DDEL-18. PEG-AU-BP NANOCARRIERS FOR DBTRG HUMAN GLIOMA CELLS
Authors: Szu-Yuan Liu, Szu-Yuan Liu
Journal: Neuro-Oncology (2022)

Abstract n-butylidenephthalide (BP) has been verified to have the superior ability of cancer cell toxicity. Furthermore, gold nanoparticles (Au) are biocompatible materials as well as the effective carrier to deliver bio-active molecular for cancer therapeutics. In present research, Au nanoparticles were firstly conjugated with polyethylene glycol (PEG), and cross-linked with BP to obtain PEG-Au-BP nanocarriers. The physicochemical properties were characterized through Ultraviolet-visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FTIR) and Dynamic light scattering (DLS) to confirm the combination of PEG,Au,and BP. Through iv vitro, normal BAEC cells and DBTRG human glioma cells were treated with PEG-Au-BP nanocarriers to investigate the cytotoxicity, cell uptake efficiency, and mechanism of endocytic routes. According to the results of MTT assay, PEG-Au-BP could significantly inhibit DBTRG cells proliferation. Cell uptake efficiency and potential cellular transportation in both BAEC and DBTRG cell lines were observed to be significantly higher at the time point of 2hr and 24 hr. Moreover, the mechanisms of endocytosis, clathrin-mediated endocytosis and cell autophagy, were explored to routes for BAEC and DBTRG cells to absorb PEG-Au-BP nanocarriers. Next, the cell progression and apoptosis of DBTRG cells after PEG-Au-BP treatment was investigated by flow cytometry. The results figured out that PEG-Au-BP could remarkably regulate DBTRG cell cycle at Sub-G1 phase as well as induced more apoptotic cells. The expression of apoptotic-related proteins in DBTRG cells was determined. After the treatment of PEG-Au-BP, the apoptotic cascade proteins, p21, BAX, Act-caspase-3 were significantly expressed in DBTRG cells. Through in vivo, the tissue morphology and particle distribution in mice were examined by retro-orbital sinus injection with PEG-Au-BP nanocarriers. The results demonstrated the tissue integrity in brain (forebrain, midbrain, cerebellum), and other organs did not show significant destruction. The above finding elucidated PEG-Au-BP to be a potential nanodrug for brain tumor therapies.
NIMG-48. MULTI-ECHO SPIN-AND-GRADIENT ECHO (SAGE) PERFUSION MRI TO EVALUATE BRAIN TUMOR MICROSTRUCTURE AND MICROVASCULATURE
Authors: Francesco Sanvito, Catalina Raymond, Nicholas S Cho, Akifumi Hagiwara, Joey Orpilla, Noriko Salamon, Timothy Cloughesy, Linda M Liau, Richard G Everson, Phioanh L Nghiemphu, Albert Lai, Robert Prins, Benjamin Ellingson
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND In a classic DSC perfusion sequence, T1 and T2* leakage effects compete in determining the post-bolus signal, and are influenced by tissue geometry (i.e. cell density, cell size). Different DSC sequences can be variously influenced by these effects, depending on the different degree of T1 weighting and the pre-bolus administration. Multi-echo spin-and-gradient echo (SAGE) perfusion MRI enables to disentangle T2* and T1 components that contribute to the classic DSC curve, and to simultaneously compute DSC and DCE perfusion metrics. METHODS We retrospectively selected patients with: diagnosis of primary brain tumor, availability of SAGE-based DSC perfusion and DWI datasets, availability of histopathological images from targeted biopsies located within contrast-enhancing tissue. Post-processing allowed to distinguish the pure T2* component from the pure T1 component, and to perform a DCE analysis on the latter. Quantitative perfusion MRI measurements were then evaluated with respect to underlying histopathology. RESULTS Histopathological images were available for 22 targeted biopsies (across 10 patients) meeting the inclusion criteria. The following novel MRI quantitative maps were successfully computed voxelwise: ΔR2* at steady state (reflecting T2* leakage effects), ΔR1 at steady state (reflecting T1 leakage effects), transverse relaxivity at tracer equilibrium (TRATE, reflecting the combination of T2* and T1 leakage effects). In addition, Ve and ktrans were computed from the DCE analysis, and the percentage of signal recovery (PSR) was computed from the second echo of the multi-echo DSC (comparable to a classic single-echo DSC sequence). CONCLUSIONS Histopathological validation will assess the usefulness of these novel multi-echo derived quantitative maps for the non-invasive prediction of tumor microstructure. This would be particularly relevant for: 1) differential diagnosis between brain tumors with different cell size and cell density (e.g. lymphoma vs glioblastoma); 2) treatment response assessment (as pre-existing studies proved that cell shrinkage is an early event in treatment response).
NCMP-23. A UNIQUE CASE OF CHOREIFORM DYSKINESIAS IN A PATIENT WITH METASTATIC RENAL CELL CARCINOMA
Authors: Ali-Musa Jaffer, Andrew Graves, Neha Verma, Sepideh Mokhtari, Yolanda Pina
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Dyskinesias in cancer patients present a diagnostic challenge to clinicians. Etiologies can include paraneoplastic syndromes, chemotherapy related side effects, or primary movement disorders. This is a unique case of choreoathetotic dyskinesias in a patient with metastatic renal cell carcinoma while undergoing treatment with cabozantinib in combination with either placebo or the investigational drug CB-839 (telanglenastat) while on the clinical trial MCC 19671. RESULTS We present a 69 year old gentleman with a history of metastatic renal cell carcinoma who developed choreoathetotic dyskinesias eleven months after enrolling in a phase 2 blind study MCC 19671. His CSF paraneoplastic panel and MRI brain imaging were unremarkable. His symptoms abated with stopping his clinical trial drug, after which he withdrew from the trial and opted to continue cabozantinib alone. Unfortunately he developed worsening dyskinesias a week after restarting cabozantinib which was then stopped permanently. He was treated with prednisone and plasma exchange with improvement in his symptoms. Unfortunately, he passed away due to progression of disease two months later. CONCLUSIONS This case highlights the first case of choreiform dyskinesias most likely associated with CB-839/cabozantinib, since the patient’s symptoms significantly improved upon stopping the medications. The patient could also have had a novel paraneoplastic-associated antibody which has not been discovered yet. As the investigation into novel chemotherapeutic agents for malignancies continues, the incidence of drug related dyskinesias will need to be monitored.
CTIM-06. EVALUATING THE ASSOCIATION BETWEEN PERIPHERAL BLOOD IMMUNOLOGIC RESPONSE AND THERAPEUTIC RESPONSE TO IMMUNE CHECKPOINT INHIBITION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA AND GLIOSARCOMA
Authors: Matthew Watowich, Nasser Yaghi, Nicole Briceno, Susie Ahn, Kathleen Wall, Karen Evans, Lily Polskin, Edina Komlodi-Pasztor, Solmaz Sahebjam, Masashi Watanabe, Mark Gilbert
Journal: Neuro-Oncology (2022)

Abstract Immune checkpoint inhibition (ICI) has failed to demonstrate significant efficacy in glioblastoma. With the underlying hypothesis that generation of an immune response in peripheral is necessary for a brain tumor response, we are enrolling patients with newly diagnosed glioblastoma on an ICI immunotherapy clinical trial with longitudinal monitoring of immune function. The purpose of this work is to improve patient selectivity for response to ICI treatment by identifying peripheral immunologic response via immunophenotyping and functional analyses. Currently, 10 of a planned 48 patients have been treated with combination nivolumab and ipilimumab (NCI-21-C-0015). We analyzed blood samples of the first two patients, from pretreatment through cycle 5 of combination ICI to confirm methods used in this clinical trial. Longitudinal evaluation of immunologic response using comprehensive flow cytometric analysis and an in vitro T cell stimulation paradigm with nivolumab and ipilimumab supplementation, serving as an ex vivo predictor of immune response, are reported. Immunophenotyping via flow cytometry successfully documented patients’ peripheral immune cell phenotypes, and ELISpot and in vitro stimulation assays successfully measured patients’ immune cell functional capacitance. Both patients analyzed have shown increased proportions of effector/memory phenotypes within peripheral T cells, and a decrease in peripheral lymphocyte/monocyte ratio during treatment, potentially indicating lymphocyte sequestration in bone marrow or recruitment to the tumor microenvironment. ELISpot analysis documented interferon-γ production capability of T cell is maintained during treatment. Moreover, preliminary analysis of patients’ T cell proliferative capacity in PBMC utilizing in vitro anti-CD3 stimulation indicated T cells become increased in proliferative capability during treatment. These findings support the feasibility of longitudinal assessments, demonstrating that immunologic responsiveness and functionality can be detected with these blood monitoring strategies. Additional patients’ samples will be tested to allow confirmation of trends in immunologic response, and correlations with patient outcomes will be reported at time of presentation.